The present invention relates to the use of neuromuscular agents, and the pharmacologically acceptable salts thereof, for the treatment of nervous system disorders, and more particularly to the use of compounds of U.S. Pat. Nos. 5,273,975, 5,436,240, 5,594,024, 5,462,947, and 4,526,892 for the treatment of symptoms of fibromyalgia syndrome and chronic fatigue syndrome.
Chronic fatigue syndrome (CFS), also referred to as chronic fatigue immune disorders syndrome, yuppie flu; fatiguexe2x80x94chronic, and chronic fatigue and immune dysfunction syndrome, is a clinically defined condition characterized by profound tiredness or fatigue. In addition, patients with CFS generally report various nonspecific symptoms, including weakness, muscle aches and pains, excessive sleep, malaise, fever, sore throat, tender lymph nodes, impaired memory and/or mental concentration, insomnia, and depression. The exact cause of CFS is unknown and, to date, there are no specific tests to confirm the diagnosis of CFS, though a variety of tests are usually done to exclude other possible causes of the symptoms.
Fibromyalgia syndrome (FMS), also referred to as fibromyalgia, fibromyositis, fibrositis, or myofasical pain syndrome, is a rheumatic condition generally characterized by widespread pain in fibrous tissues, muscles, tendons, and other connective tissues, fatigue, headaches, lack of restorative sleep, and numbness. Thus, FMS shares many clinical features with CFS. Similar to CFS, there are no specific diagnostic tests for FMS.
Many medications are commonly used to treat CFS and FMS. Examples of the more common medications include hypnotics, immune suppressants, various other prescribed medications, and an array of non-prescription medications. Examples of other prescription drugs include opioid antagonists, sodium retention agents/beta blockers, calcium channel blockers/histamine blockers, anti-depressants, allergy medications, and acute anxiety medications. However, there are no known medications that permanently resolve the symptoms of either CFS or FMS. In addition, many of the currently used medications produce side effects ranging from mild side effects, e.g., drowsiness, dizziness, and nausea to serious side effects, e.g., addiction and liver damage
Accordingly, there is clearly a need for better treatments for chronic fatigue syndrome and fibromyalgia. Now, the present invention reveals several compounds that can be formulated into useful therapeutic treatments for these conditions.
Disclosed is a method of treating symptoms of fibromyalgia syndrome or chronic fatigue syndrome which comprises administering to a patient in need of treatment a therapeutically effective amount of a heterocyclic amine-type compound of formula (A), 
or a pharmaceutically acceptable salt thereof, wherein:
R1, R2, and R3 are independently hydrogen, C1-6 alkyl, C3-5 alkenyl, C3-5 alkynyl, C3-7 cycloalkyl, C4-10 cycloalkyl or phenyl-substituted C1-6 alkyl, or R1 and R2 are joined to form a C3-7 cyclic amine which can contain additional heteroatoms and/or unsaturation;
X is hydrogen, C1-6 alkyl, halogen, hydroxy, alkoxy, cyano, carboxamide, carboxyl, or carboalkoxyl;
A is CH, CH2, CH-halogen, CHCH3, Cxe2x95x90O, Cxe2x95x90S, Cxe2x80x94SCH3, Cxe2x95x90NH, Cxe2x80x94NH2, Cxe2x80x94NHCH3, Cxe2x80x94NHCOOCH3, Cxe2x80x94NHCN, SO2, or N;
B is CH2, CH, CH-halogen, Cxe2x95x90O, N, NH or Nxe2x80x94CH3, or O;
n is 0 or 1; and
D is CH, CH2, CH-halogen, Cxe2x95x90O, O, N, NH, or Nxe2x80x94CH3.
Preferred compounds of formula (A) include (R)-5,6-Dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]-quinolin-2(1H)-one (uninverted CAS name) and (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione, and their pharmaceutically acceptable salts. Also disclosed is a method of treating symptoms of fibromyalgia syndrome or chronic fatigue syndrome which comprises administering to a patient in need of treatment a therapeutically effective amount of a substituted phenylazacycloalkane-type compound of formula (B), 
or pharmaceutically acceptable salts thereof, wherein:
n is 0-3;
R1 and R2 are independently H (provided only one is H at the same time), xe2x80x94OH (provided R4 is other than hydrogen), CN, CH2CN, 2- or 4-CF3, CH2CF3, CH2CHF2, CHxe2x95x90CF2 (CH2)2CF3, ethenyl, 2-propenyl, OSO2CH3, OSO2CF3, SSO2CF3, COR4, COOR4, CON(R4)2, SOxCH3 (where, x is 0-2), SOxCF3, O(CH2)xCF3, SO2N( COCOOR4, COCOON(R4)2, C1-8 alkyls, C3-8 cycloalkyls, CH2OR4, CH2(R4)2, NR4SO2CF3, NO2, halogen, a phenyl at positions 2, 3 or 4, thienyl, furyl, pyrrole, oxazole, thiazole, N-pyrroline, triazole, tetrazole or pyridine;
R3 is hydrogen, CF3, CH2CF3, C1-C8 alkyl, C3-C8 cycloalkyl, C4-C9 cycloalkyl-methyl, C2-C8 alkenyl, C2-C8 alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, xe2x80x94(CH2)mxe2x80x94R5 (where m is 1-8), CH2SCH3 or a C4-C8 alkyl bonded to said nitrogen and one of its adjacent carbon atoms inclusive to form a cyclic structure;
R4 is independently hydrogen, CF3, CH2CF3, C1-C8 alkyl, C3-C8 cycloalkyl, C4-C9cycloalkyl-methyl, C2-C8 alkenyl, C2-C8 alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, xe2x80x94(CH2)mxe2x80x94R5 where m is 1-8;
R5 is phenyl, phenyl (substituted with a CN, CF3, CH2CF3, C1-C8 alkyl, C3-C8 cycloalkyl, C4-C9 cycloalkyl-methyl, C2-C8 alkenyl, C2-C8 alkynyl), 2-thiophenyl, 3-thiophenyl, xe2x80x94NR6CONR6R7, or xe2x80x94CONR6R7:
R6 and R7 are independently hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, C4-C9 cycloalkyl, methyl, C2-C8 alkenyl or C2-C8 alkynyl; and with the proviso that when R1 is 2-CN or 4-CN, R2 is H, R3 is n-Pr and n is 1 or 3 then such compound is a pure enantiomer.
Preferred compounds of formula (B) include (3S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride, (3S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrobromide, and (3S)-3-[3-Methylsulfonyl)phenyl]-1-propylpiperidine (2E)-2-butenedioate (1:1).
Further disclosed is a method of treating symptoms of fibromyalgia syndrome or chronic fatigue syndrome which comprises administering to a patient in need of treatment a therapeutically effective amount of a cabergoline-type compound, or pharmaceutically acceptable salts thereof, with the preferred compound of this class being cabergoline.
The present invention relates to therapies for fibromyalgia (FMS) and chronic fatigue syndrome (CFS), and more particularly to the use of three broad classes of compounds having dopamine receptor activities for treating the symptoms of FMS and CFS. The useful compounds identified for the method of the present invention are described in two ways, with generic descriptions of completely enabled and disclosed groups of compounds and with detailed individually described compound structures and names. One class of compounds useful for treating symptoms of CFS and FMS in the present invention are those compounds, or pharmaceutically acceptable salts thereof, di-closed generically or specifically in U.S. Pat. Nos. 5,273,975 and 5,436,240. These compounds are generically referred to as heterocyclic amine type compounds and are structurally represented by formula (A), 
wherein:
R1, R2, and R3 are independently and are hydrogen, C1-6 alkyl, C3-5alkenyl, or C3-5 alkynyl, C3-7 cycloalkyl, C4-10 cycloalkyl- or phenyl-substituted C1-6 alkyl, or R1 and R2 are joined to form a C3-7 cyclic amine which can contain additional heteroatoms and/or unsaturation;
X is hydrogen, C1-6 alkyl, halogen, hydroxy, alkoxy, cyano, carboxamide, carboxyl, or carboalkoxyl;
A is CH, CH2, CH-halogen, CHCH3, Cxe2x95x90O, Cxe2x95x90S, Cxe2x80x94SCH3, Cxe2x95x90NH, Cxe2x80x94NH2, Cxe2x80x94NHCH3, Cxe2x80x94NHCOOCH3, or Cxe2x80x94NHCN, SO2, or N;
B is CH2, CH, CH-halogen, Cxe2x95x90O, N, NH, Nxe2x80x94CH3 or O;
n is 0 or 1; and
D is CH, CH2, CH-halogen, Cxe2x95x90O, O, N, NH or Nxe2x80x94CH3.
The methods oft making the compounds and the pharmaceutically preparations are described in U.S. Pat. Nos. 5,273,975 and 5,436,240, and in International Patent Application WO 00/40226. The full disclosure of the above-cited U.S. Pat. Nos. 5,273,975 and 5,436,240 and International Patent Application WO 00/40226 is incorporated herein by reference.
An especially preferred compound of formula (A) in the present invention is a compound of formula (Aa), 
or pharmaceutically acceptable salt thereof. The compound name for the compound of formula (Aa) is (R)-5,6-Dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]-quinolin-2(1H)-one (uninverted CAS name) or (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (Generated by ACD/Name software).
It is preferred that (R)-5,6-Dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]-quinolin-2(1H)-one be present in a pharmaceutically acceptable salt. Suitable pharmaceutically acceptable salts include salts of both inorganic and organic acids; examples include without limitation salts of the following acids: hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, citric, methanesulfonic, CH3xe2x80x94(CH2)n1xe2x80x94COOH where n1 is 0 thru 4, HOOCxe2x80x94(CH2)n1xe2x80x94COOH where n is as defined above, HOOCxe2x80x94CHxe2x95x90CHxe2x80x94COOH, and xcfx86xe2x80x94COOH. For other acceptable salts, see Int. J. Pharm., 33, 201-217 (1986). A particularly preferred salt of (R)-5,6-Dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]-quinolin-2(1H)-one is the maleate, i.e. (Z)-2-butenedioate, salt, which is (R)-5,6-Dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]-quinolin-2(1H)-one (Z)-2-butenedioate (1:1). The (Z)-2-butenedioate salt is shown as formula (Ab): 
Another group of compounds within the generic formula of the heterocyclic amine-type compounds shown above, are selected heterocyclic amine compounds, the most preferred being (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione, a compound of the formula (Ac) below, also referred to herein at formula (VIII), 
or pharmaceutically acceptable salts thereof.
U.S. Pat. No. 5,273,975 generically discloses and claims (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione, but does not give an example or specific mention of this compound. (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione (VIII) is preferably made from the corresponding non-thio analog, (5R)-(methylamino)-5,6-dihydro-4H-imidao(4,5,1-ij)quinolin-(2H)-one (VII). A preferred process of making (5R)-(Methylamino)-5,6-dihydro-4H-imidao(4,5,1-ij)quinolin-(2H)-one (VII) is illustrated in PREPARATION 1 and EXAMPLEs 1-6, as well as CHART A. The preferred method of transforming (5R)-(methylamino)-5,6-dihydro-4H-imidao(4,5,1-ij)quinolin-(2H)-one (VII) into (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione (VIII) is set forth in EXAMPLE 8.
It is prepared that (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione (IX) be present as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include salts of both inorganic and organic acids. The preferred pharmaceutically acceptable salts include salts of the following acids hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, citric, methanesulfonic CH3xe2x80x94(CH2)n1xe2x80x94COOH where n1 is 0 thru 4, HOOCxe2x80x94(CH2)n1xe2x80x94COOH where n is as defined above, HOOCxe2x80x94CHxe2x95x90CHxe2x80x94COOH, xcfx86xe2x80x94COOH. For other acceptable salts, see Int. J. Pharm., 33, 201-217 (1986). It is more preferred that (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione be present as the maleate salt, which is (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione maleate. The maleate salt is shown below as formula (Ad) or formula (IX): 
Conventional pharmaceutical preparations can be used for the heterocyclic amine-type compounds, e.g., consisting essentially of an inert pharmaceutical carrier and an effective dose of the active substance. Suitable dosages forms include without limitation plain or coated tablets, capsules, lozenges, powders, solutions, suspensions, emulsions, syrups, suppositories, transdermal patch, etc, with tablet being the preferred dosage form.
The effective dose range for oral administration of a heterocyclic amine-type compound is from about 0.30 through about 50.0 mg/dose/patient orally. Patients with milder forms of FMS or CFS would be expected to need less drug, while patients with more severe forms of the disease may be expected to need more drug. The dosages to be given to a particular patient should be easily determined by a skilled physician with experience in prescribing biologically active drugs designed to modulate central nervous system, movement and related psychological and physiological disorders of the type described here. Normally the drug is given once a day or twice a day, it may be given even less often for some patients.
Another class of compounds useful in the present invention are those compounds, or pharmaceutically acceptable salts thereof, disclosed generically or specifically in U.S. Pat. Nos. 5,594,024 and 5,462,947, both incorporated by reference herein. These compounds are generically referred to as substituted phenylazacycloalkane-type compounds and are structurally represented by formula (B), 
wherein:
n is 0-3;
R1 and R2 are independently H (provided only one is H at the same time), xe2x80x94OH (provided R4 is other than hydrogen), CN, CH2CN, 2- or 4CF3, CH2-CF3, CH2CHF2, CHxe2x95x90CF2, (CH2)2CF3, ethenyl, 2-propenyl, OSO2CH3, OSO2CF3, SSO2CF3, COR4, COOR4, CON(R4)2, SOxCH3 (where, x is 0-2), SOxCF3, O(CH2)xCF3, SO2N(R4)2,CHxe2x95x90NOR4, COCOOR4, COCOON(R4)2, C1-8 alkyls, C3-8 cycloalkyls, CH2OR4, CH2(R4)2, NR4SO2CF3, NO2, halogen, a phenyl at positions 2, 3 or 4, thienyl, furyl, pyrrole, oxazole, thiazole, N-pyrroline, triazole, tetrazole or pyridine;
R3 is hydrogen, CF3, CH2CF3, C1-C8 alkyl, C3-C8 cycloalkyl, C4-C9 cycloalkyl-methyl, C2-C8 alkenyl, C2-C8 alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, xe2x80x94(CH2)mxe2x80x94R5(where m is 1-8), CH2SCH3 or a C4-C8 alkyl bonded to said nitrogen and one of its adjacent carbon atoms inclusive to form a cyclic structure;
R4 is independently hydrogen, CF3, CH2CF3, C1-C8 alkyl, C3-C8 cycloalkyl, C4-C9cycloalkyl-methyl, C2-C8 alkenyl, C2-C8 alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, xe2x80x94(CH2)mxe2x80x94R5 where m is 1-8;
R5 is phenyl, phenyl (substituted with a CN, CF3, CH2CF3, C1-C8 alkyl, C3-C8 cycloalkyl, C4-C9 cycloalkyl-methyl, C2-C8 alkenyl, C2-C8 alkynyl), 2-thiophenyl, 3-thiophenyl, xe2x80x94NR6CONR6R7, or xe2x80x94CONR6R7;
R6 and R7 are independently hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, C4-C9 cycloalkyl-methyl C2-C8 alkenyl or C2-C8 alkynyl; and with the proviso that when R1 is 2-CN or 4-CN, R2 is H, R3 is n-Pr and n is 1 or 3 then such compound is a pure enantiomer.
Also useful in the present invention are pharmaceutically acceptable salts of compounds of formula (B), those salts being disclosed in U.S. Pat. Nos. 5,462,947 and 5,594,024, both incorporated herein by reference. Both organic and inorganic acids can be employed to form pharmaceutically acceptable salts; illustrative acids include sulfuric, nitric, phosphoric, hydrochloric, citric, acetic, lactic, ethanedisulfonic, sulfamic, succinic, cyclohexylsulfamic, fumaric, maleic, and benzoic acids. These salts are readily prepared by methods known in the art.
A particularly suitable compound of formula (B) in the present invention is (3S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride (uninverted CAS name) or OSU 6162 or (3S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride (Generated by ACD/Name software), and is represented by formula (Ba): 
Another particularly suitable compound of formula (B) in the present invention is (3S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrobromide (uninverted CAS name) or (3S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrobromide (Generated by ACD/Name software), and is represented by formula (Bb): 
Yet another particularly suitable compound of formula (B) in the present invention is (3S)-3-[3-Methylsulfonyl)phenyl]-1-propylpiperidine (2E)-2-butenedioate (1:1) (uninverted CAS name) or (S)-OSU6162, and is represented by formula (Bc): 
The methods of preparing these compounds, and formulations and medicaments of the same, are described in U.S. Pat. Nos. 5,594,024 and 5,462,947, both incorporated herein by reference.
Conventional pharmaceutical preparations can be used for the substituted phenylazacycloalkane-type compounds, e.g., consisting essentially of an inert pharmaceutical carrier and an effective dose of the active substance; e.g., plain or coated tablets, capsules, lozenges, powders, solutions, suspensions, emulsions, syrups, suppositories, transdermal patch, etc. Preferred dosage forms are tablets.
The effective dose range for oral administration of a substituted phenylazacycloalkane-type compound is from about 10 to about 1000 mg/dose/patient once or twice a day. The dosage and dose frequency for a particular patient should be easily determined by a skilled physician with experience in prescribing biologically active drugs designed to modulate central nervous system, movement and related psychological and physiological disorders of the type described here. While normally the drug may be given once a day or twice a day, it may be given even less often for some patients.
A further class of compounds useful in the present invention are those compounds, or pharmaceutically acceptable salts thereof, disclosed generically or specifically in U.S. Pat. No. 4,526,892, the full disclosure of which is incorporated herein by reference. These compounds are generically referred to as cabergoline-type compounds. The preferred compound in this class is cabergoline itself, or its pharmaceutically acceptable salts. The chemical name for cabergoline is 1-((6-allylergolin-8xcex2-yl)-carbony.)-1-(3-(dimethylamino)propyl)-3-ethylurea and the structure of carbergoline is represented by formula (C): 
Cabergoline is the generic name for the active ingredient in DOSTFNEX(copyright) or CABASER(copyright) Tablets, which are marketed by Pharmacia and Upjohn, Inc. in the United States, Europe and Latin America as a treatment for hyperprolactinemic disorders and Parkinson""s disease. The synthesis and use of cabergoline is disclosed and claimed in U.S. Pat. No. 4,526,892, which is incorporated here-in by reference.
Conventional pharmaceutical preparations can be used for cabergoline, e.g., consisting essentially of an inert pharmaceutical carrier and an effective dose of the active substance, e.g., plain or coated tablets, capsules, lozenges, powders, solutions, suspensions, emulsions, syrups, suppositories, etc, with tablet being the preferred dosage form.
A package insert describing CABASER(copyright), its pharmacokinetics, clinical studies, indications and usage, contraindication and warnings, and Parkinson""s disease patients is provided by Pharmacia and Upjohn, Inc. This package insert and its descriptions are incorporated by reference into this application.
The effective dose range for cabergoline is from about 0.01 to about 10.0 mg/dose/patient, preferably from about 0.25 to about 10.0 mg/dose/patient, more preferably from about 1 to about 6 mg/dose/patient, and even more preferably from about 1 to about 2 mg/dose/patient orally. At these dose levels above, cabergoline is typically administered once or twice a day; however, for some patients the dose frequency may be reduced to three times a week, two times a week or even once a week. The combination of dosage levels and dose frequency for a particular patient may be readily adjusted by the treating physician.
The dose response to cabergoline in terms of efficacy and side effects appears to be mainly linked to individual sensitivity. Under some circumstances and with the appropriate patients, dose optimization may be obtained, for example, by administering a low initial dose of cabergoline to the patient at a dose of 0.5 to 1 mg/patient/day and adjusting the dose upward at weekly intervals to an optimal therapeutic dosage of 2, 4, 6, 8 or 10 mg/patient/day. Patients with milder forms of the disease would be expected to need less drug. For example, in some cases a dose of 0.05, 0.1 or even 0.25 mg/patient may be adequate. Patients with more severe forms of the disease and those who have been treated with other dopaminergic agents may be expected to need more drug. The precise dosage would be readily determined by the treating physician evaluating such factors as the progression of the state of the disease, the weight and age of the patient, whether and to what extent other drugs such as L-Dopa or levodopa were administered, and other such factors as are typically evaluated by a physician before determining the dosage of a CNS drug to a patient.
The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims.
All temperatures are in degrees Celsius.
TLC refers to thin-layer chromatography.
HPLC refers to high pressure liquid chromatography.
Saline refers to an aqueous saturated sodium chloride solution.
Chromatography (column and flash chromatography) refers to purification/separation of compounds expressed as (support, eluent). It is understood that the appropriate fractions are pooled and concentrated to give the desired compound(s).
IR refers to infrared spectroscopy.
CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts are reported in ppm (xcex4) downfield from TMS.
NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemical shifts are reported in ppm (xcex4) downfield from tetramethylsilane.
xcfx86 refers to phenyl (C6H5).
[xcex1]D25 refers to the angle of rotation of plane polarized light (specific optical rotation) at 25xc2x0 with the sodium D line (589A).
MS refers to mass spectrometry expressed as m/e, m/z or mass/charge unit. [M+H]+ refers to the positive ion of a parent plus a hydrogen atom. EI refers to electron impact. CI refers to chemical ionization. FAB refers to fast atom bombardment.
Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
When solvent pairs are used, the ratios of solvents used are volume/volume (v/v).
When the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weight/volume (wt/v).